This application proposes to address a fundamental unresolved question in the field of cognitive aging, the nature of the neurobiological factors that distinguish individuals with healthy cognitive aging (HCA) from those with unhealthy cognitive aging (UCA). The focus of the studies will be on biomarkers developing near the age of divergence of unhealthy from healthy cognitive aging, as these appear particularly likely to provide important insights into causal mechanisms. A major emphasis of the project will also be testing the hypothesis that midlife activation of myelinogenic programs in the hippocampus is an important factor in converting HCA to UCA. This view derives from our recent work with both microarray and immunohistochemical techniques showing that myelinogenesis is increased around midlife in rats, the same age range in which unhealthy cognitive aging begins to appear. The proposed studies will comprise a large multidisciplinary project aimed at obtaining a unique integrated perspective on neurobiological correlates of cognitive aging in an established rat model of aging. It will involve state-of-the-art intracellular electrophysiology in hippocampal slices, concomitant Ca2+ imaging in recorded neurons, extensive immunohistochemistry with a battery of stains, diffusion tensor imaging (MRI/DTI), separate microarray analysis of each individual rat, and substantial behavioral testing of each animal. Multiple techniques will be applied in each animal. These studies will pursue the aims of correlating electrophysiological and genomic markers of cognitive aging in the same animals and will relate cognitive function to myelin structure and density in cross-sectional and longitudinal analyses. Further, the course of myelinogenesis will be altered in long-term studies that manipulate dietary iron and/or treat with cuprizone. Animals subjected to altered myelinogenesis will be tested on a battery of behavioral, electrophysiological, microarray and immunohistochemical analyses, to test the proposition that conversion to UCA has been slowed and, if it has, to determine through which hippocampal pathways this occurred. Overall, these studies should substantially elucidate neurobiological markers distinguishing UCA from HCA, and should importantly determine the role of myelinogenic programs in cognitive aging. Further, the proposed longitudinal studies should have direct translational relevance.